Faculty Profiles - TAKIGAWA Masaharu

Papers - TAKIGAWA Masaharu

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CT domain of CCN2/CTGF directly interacts with fibronectin and enhances cell adhesion of chondrocytes through integrin alpha 5 beta 1

M Hoshijima, T Hattori, M Inoue, D Araki, H Hanagata, A Miyauchi, M Takigawa

FEBS LETTERS 580 ( 5 ) 1376 - 1382 2006.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Searching for CCN family protein 2/connective tissue growth factor (CCN2/CTGF) interactive proteins by yeast-two-hybrid screening, we identified fibronectin 1 gene product as a major binding partner of CCN2/CTGF in the chondrosarcoma-derived chondrocytic cell line HCS-2/8. Only the CT domain of CCN2/CTGF bound directly to fibronectin (FN). CCN2/CTGF and its CT domain enhanced the adhesion of HCS-2/8 cells to FN in a dose-dependent manner. The CCN2/CTGF-enhancing effect on cell adhesion to FN was abolished by a blocking antibody against alpha 5 beta 1 integrin (alpha 5 beta 1), but not by one against anti-alpha v beta 3 integrin. These findings suggest for the first time that CCN2/CTGF enhances chondrocyte adhesion to FN through direct interaction of its C-terminal CT domain with FN, and that alpha 5 beta 1 is involved in this adhesion. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2006.01.061

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Cartducin, a paralog of Acrp30/adiponectin, is induced during chondrogenic differentiation and promotes proliferation of chondrogenic precursors and chondrocytes

T Maeda, A Jikko, M Abe, T Yokohama-Tamaki, H Akiyama, S Furukawa, M Takigawa, S Wakisaka

JOURNAL OF CELLULAR PHYSIOLOGY 206 ( 2 ) 537 - 544 2006.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

We previously reported that CORS26 gene, isolated from C3H10T1/2 cells treated with transforming growth factor-beta 1, was predominantly expressed in cartilage. Because the gene product is a kind of secretory protein produced by cartilage tissue, we named it "cartducin". Cartducin shares a similar modular organization to adipocyte-derived hormone, adiponectin. In this Study, we investigated cartducin function during chondrogenesis and cartilage development. In situ hybridization analysis showed that cartducin transcripts were restricted to the proliferating chondrocytes in the growth plate cartilage. Whole-mount in situ hybridization revealed that the first significant induction of cartducin expression occurred in the sclerotome, which contains a chondrogenic cell lineage between days 9.5 and 10.5 postcoitus (p.c.) during mouse embryogenesis. Chondrogenic differentiation by combined treatment with bone morphogenetic protein-2 and insulin induced cartducin expression along with type II and IX collagen expression in chondrogenic progenitor N1511 cells. To elucidate the direct action of cartducin on the cells, recombinant cartducin protein was expressed in and purified from Escherichia coli. The recombinant cartducin potentially forms homo-oligomers and promoted the proliferation of chondrogenic progenitor N1511 cells, and chondrocytic HCS-2/8 cells in a dose-dependent manner. On the other hand, cartducin did not affect the production of sulfated glycosarninoglycan (sGAG) in these cells. These findings indicate that cartducin is a novel growth factor and plays important roles in regulating both chondrogenesis and cartilage development by its direct stimulatory action on the proliferation of chondrogenic precursors and chondrocytes.

DOI： 10.1002/jcp.20493

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Novel angiogenic inhibitor DN-9693 that inhibits post-transcriptional induction of connective tissue growth factor (CTGF/CCN2) by vascular endothelial growth factor in human endothelial cells

S Kondo, N Tanaka, S Kubota, Y Mukudai, G Yosimichi, T Sugahara, M Takigawa

MOLECULAR CANCER THERAPEUTICS 5 ( 1 ) 129 - 137 2006.1

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Connective tissue growth factor (CTGF/CCN2) is a potent angiogenic factor. In this report, we describe for the first time that vascular endothelial growth factor (VEGF)mediated induction of the ctgf/ccn2 gene was a posttranscriptional event that was inhibited by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells. Steady-state mRNA levels of ctgf/ccn2 were remarkably increased by VEGF in a concentration-dependent manner, whereas the activity of the ctgf/ccn2 promoter was not responsive to VEGF as confirmed by a reporter gene assay and quantitative real-time PCR analysis. By employing a RNA degradation assay, we eventually found that the observed increase in the ctgf/ccn2 mRNA level was due to an increased stability of the mRNA induced by VEGF. DN-9693 at a dose of 0.1 to 2 ng/mL did not affect basal levels of ctgf/ccn2 mRNA; however, enhancement of ctgf/ccn2 mRNA expression by VEGF was specifically inhibited by DN-9693. Of importance, the inhibitory effects could be also ascribed to post-transcriptional regulation, because the VEGF-mediated increase in stability of ctgf/ccn2 mRNA was suppressed by DN-9693. Furthermore, we investigated the effects of DN-9693 on VEGF-induced activation of three subgroups of mitogen-activated protein kinase pathways and found that DN-9693 blocked the activation of these pathways by VEGF. These results suggest that VEGF increases ctgf/ccn2 mRNA stability through mitogen-activated protein kinase-mediated intracellular signaling cascade(s), which can be inhibited posttranscriptionally by a novel angiogenic inhibitor, DN-9693, in human umbilical vein endothelial cells.

DOI： 10.1158/1535-7163.MCT-05-0097

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軟骨組織の発生分化とCCNファミリー遺伝子

久保田聡, 滝川正春

Clinical Calcium 16,486-492 2006

関節リウマチにおける自己抗原と分子シャペロン?軟骨細胞におけるその役割

服部高子, 滝川正春

Clinical Calcium 16,1553-1556 ( 9 ) 1553 - 1556 2006

Language：Japanese Publisher：(株)医薬ジャーナル社

小胞体シャペロンheat shock protein/rheumatoid arthritis-related antigen(HSP47/RA-A47)は細胞内のコラーゲン成熟、分泌の機能を持ち、細胞をストレスから防御し、未成熟あるいは正常な合成に失敗したコラーゲンの細胞外への分泌を妨げる役割を担っているが、リウマチ軟骨ではその発現量が減少しており、細胞に小胞体ストレスを誘発している。また、軟骨細胞破壊につながる細胞障害性因子の放出を促し、その結果軟骨細胞はアポトーシスにより死ぬ。また、この時細胞外にHSP47/RA-A47が放出される。細胞外HSP47/RA-A47は自己抗原として認識される可能性があるが、抗原抗体反応およびそれにかかわる炎症反応を制御している可能性もある。HSP47/RA-A47の細胞内外の量のコントロールがリウマチ治療の鍵となろう。(著者抄録)

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Expression and regulation of an antisense RNA transcript of the human connective tissue growth factor gene in human tumour cells

Seiji Kondo, Satoshi Kubota, Harumi Kawaki, Norifumi Moritani, Toshimasa Kagawa, Takaaki Ueno, Toshio Sugahara, Masaharu Takigawa

Asian Journal of Oral and Maxillofacial Surgery 18 ( 3 ) 172 - 179 2006

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Communications International Ltd

Objective: To characterise a natural antisense transcript of connective tissue growth factor. Materials and Methods: RNA from several cell lines was analysed by RNase protection assay to detect antisense transcripts. To characterise the regulatory aspect of the transcribed area, chimeras were constructed in which the firefly luciferase gene was fused with the corresponding segment of ctgf/ccn2, and the gene expression was monitored. Results: A natural antisense transcript complementary to the 3′-untranslated region of ctgf/ccn2 mRNA in cultured human tumour cells was detected. The luciferase gene fused with the full-length antisense 3′-untranslated region showed strikingly low levels of luciferase expression compared with the control. Based on a series of deletion analyses, the major repressive element was located in the middle portion within the 3′-untranslated region, which corresponded to the antisense transcribed area. Conclusion: These results suggest that controlled expression of antisense RNAs against the 3′-untranslated region of ctgf/ccn2 mRNA may be involved in the determination of phenotypes in certain oral malignancies. © 2006 Asian Association of Oral and Maxillofacial Surgeons.

DOI： 10.1016/S0915-6992(06)80014-2

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Effect of connective tissue growth factor (CCN2/CTGF) on proliferation and differentiation of mouse periodontal ligament-derived cells

Masahiro Asano, Satoshi Kubota, Tohru Nakanishi, Takashi Nishida, Tomoichiro Yamaai, Gen Yosimichi, Kazumi Ohyama, Tomosada Sugimoto, Yoji Murayama, Masaharu Takigawa

Cell Communication and Signaling 3 11(Epub) 2005.10

Language：English Publishing type：Research paper (scientific journal)

Background: CCN2/CTGF is known to be involved in tooth germ development and periodontal tissue remodeling, as well as in mesenchymal tissue development and regeneration. In this present study, we investigated the roles of CCN2/CTGF in the proliferation and differentiation of periodontal ligament cells (murine periodontal ligament-derived cell line: MPL) in vitro. Results: In cell cultures of MPL, the mRNA expression of the CCN2/CTGF gene was stronger in sparse cultures than in confluent ones and was significantly enhanced by TGF-β. The addition of recombinant CCN2/CTGF (rCCN2) to MPL cultures stimulated DNA synthesis and cell growth in a dose-dependent manner. Moreover, rCCN2 addition also enhanced the mRNA expression of alkaline phosphatase (ALPase), type I collagen, and periostin, the latter of which is considered to be a specific marker of the periosteum and periodontium
whereas it showed little effect on the mRNA expression of typical osteoblastic markers, e.g., osteopontin and osteocalcin. Finally, rCCN2/CTGF also stimulated ALPase activity and collagen synthesis. Conclusion: These results taken together suggest important roles of CCN2/ CTGF in the development and regeneration of periodontal tissue including the periodontal ligament. © 2005 Asano et al
licensee BioMed Central Ltd.

DOI： 10.1186/1478-811X-3-11

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The human chondrosarcoma HCS-2/8 cell line is responsive to BMP-7, but not to IL-1beta

J Saas, M Gebauer, C Jacobi, J Haag, M Takigawa, T Aigner

FRONTIERS IN BIOSCIENCE 10 2027 - 2035 2005.9

Language：English Publishing type：Research paper (scientific journal) Publisher：FRONTIERS IN BIOSCIENCE INC

Cultures of primary chondrocytes as in vitro model systems for studying the cellular behavior of chondrocytes are notoriously difficult to cultivate and propagate. One way to circumvent these problems appears to be the use of immortalized/immortal chondrocytic cell lines. In the present study, we were interested whether the chondrosarcoma derived HCS-2/8 cells are suitable for studying major cellular reaction pattern in response to key anabolic (BMP-7) and catabolic (IL-1beta) factors. Therefore, we used cDNA array and real-time PCR technology in order to evaluate gene expression triggerd by stimulation with IL-1beta (0,1-100 ng/ml) and BMP-7 in confluent monolayer cultures. HCS-2/8 cells hardly responded to IL-1beta, but showed good responsiveness to BMP-7. We found 12 genes up- and 17 significantly down-regulated by BMP-7 ( out of 340 investigated genes). Besides the expected activation of anabolic genes chondrocytic cells after BMP-stimulationtry to neutralize activation of the BMP-signalling cascade by expressing intra- and extracellular BMP-antagonists. Chondrosarcoma derived cell lines are a potential substitute for primary articular chondrocytes promising consistent expression of a differentiated chondrocyte phenotype with sufficient proliferative capacity. However, as shown by this study one needs to carefully select the cell line depending on the effects which one intends to study. In this respect, HCS-2/8 cells are a validated tool for studying BMP-effects on chondrocytes, but not e. g. effects of interleukin-1.

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軟骨細胞におけるCCN familyメンバーのdexahamethasoneによる遺伝子発現調節

川木晴美, 久保田聡, 近藤誠二, 滝川正春

Journal of Oral Biosciences 47 ( Suppl. ) 86 - 86 2005.9

新規血管新生阻害剤DN-9693の作用機序 VEGFによる血管新生因子CTGF/CCN2の発現レベルの上昇に対する阻害効果

近藤誠二, 田中紀子, 久保田聡, 菅原利夫, 滝川正春

日本癌学会総会記事 64回 134 - 134 2005.9

ヒト軟骨肉腫由来軟骨細胞株 (HCS-2/8)におけるWnt誘導分泌タンパク質1 (Wisp1/CCN4)mRNAスプライス変異体(Writ-induced secreted protein 1(Wispl/CCN4) mRNA splicing variants in a human chondrosarcoma-derived chondrocytic cell line (HCS-2/8))

Yanagita Takeshi, Kubota Satoshi, Hattori Takako, Hoshijima Mitsuhiro, Kawata Kazumi, Takano-Yamamoto Teruko, Takigawa Masaharu

生化学 77 ( 8 ) 1014 - 1014 2005.8

Gene expression of connective tissue growth factor (CTGF/CCN2) in calcifying tissues of normal and cbfa1-null mutant mice in late stage of embryonic development

T Yamaai, T Nakanishi, M Asano, K Nawachi, G Yoshimichi, K Ohyama, T Komori, T Sugimoto, M Takigawa

JOURNAL OF BONE AND MINERAL METABOLISM 23 ( 4 ) 280 - 288 2005.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Connective tissue growth factor (CTGF/CCN2), one of the most recently described growth factors, is produced by chondrocytes, vascular endothelial cells, and transforming growth factor (TGF)-beta-stimulated fibroblasts. CTGF was isolated from a chondrosarcoma-derived chondrocytic cell line, HCS-2/8, and found to be normally expressed in cartilage tissues, especially in hypertrophic chondrocytes, and also to stimulate both the proliferation and the differentiation of chondrocytes in vitro. Therefore, CTGF is thought to be one of the most important regulators of endochondral ossification in vivo. Herein we describe the expression pattern of the ctgf gene in the calcifying tissues of normal developing mouse embryos in comparison with that in core binding factor a1 (Cbfa1)-targeted mutant (cbfa1-null) mouse embryos, in which impaired development and growth were characteristically observed in the skeletal system. After 15 days of development (E15), the expression of ctgf was detected in the zone of hypertrophy and provisional calcification, in which ossification proceeds toward the epiphysis during the skeletal development of the mouse embryo. Furthermore, ctgf was expressed in developing molar and incisal tooth germs around the perinatal stage. However, no expression of the gene was found in the cbfa1-null mouse embryos. These results indicate that CTGF may have certain important roles in the development of the calcifying tissues in the mouse embryo.

DOI： 10.1007/s00774-004-0600-5

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Translational repression by the cis-acting element of structure-anchored repression (CAESAR) of human ctgf/ccn2 mRNA

S Kubota, Y Mukudai, NH Moritani, K Nakao, K Kawata, M Takigawa

FEBS LETTERS 579 ( 17 ) 3751 - 3758 2005.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

The cis-acting element of structure-anchored repression (CAESAR) is a post-transcriptional regulatory element of gene expression, which is located in the 3'-untranslated region (UTR) of the human ccn2 gene (ctgflccn2). In this report, the repression mechanism of CAESAR, as well as the structural requirement, was investigated. Removal of minor stem-loops from CAESAR resulted in proportional attenuation of the repressive function, whereas removal of the single bulge or modification of primary nucleotide sequence did not affect its functionality. In light of functional mechanism, CAESAR exerted no significant effects on stability or nuclear export of the cis-linked mRNA. However, this element significantly interfered with the association of such mRNA on ribosome and slowed down the translation process thereafter in vitro. A translation repression mechanism by RNA secondary structure to determine the basal ctgflccn2 expression level was uncovered herein. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2005.05.068

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CONNECTIVE TISSUE GROWTH FACTOR MEDIATES PROFIBROTIC EFFECTS OF TRANSFORMING GROWTH FACTOR-B PRODUCED BY TUBULAR EPITHELIAL CELLS IN RESPONSE TO HIGH GLUCOSE

Nobutaka Kato, Hirokazu Okada, Tatsuya Kobayashi, Tsutomu Inoue, Tomohiro Kikuta, Yoshihiko Kanno, Yusuke Watanabe, Soichi Sugahara, Hitoshi Hoshi, Keita Sueyoshi, Hiromichi Suzuki

NEPHROLOGY 10 A24 - A24 2005.6

二次骨化中心形成過程に発現する結合組織成長因子CTGF/CCN2のパールカン陽性軟骨細胞への特異的集積

岡森彦, 久保田聡, 近藤誠二, 江口傑徳, 河田かずみ, 黒田知沙, 皆木省吾, 滝川正春

日本骨代謝学会学術集会プログラム抄録集 23回 229 - 229 2005.6

低酸素組織,軟骨における肥大軟骨特異的蛋白24/結合組織成長因子/CCNファミリー2mRNAの安定化機構核および細胞質タンパク結合を介した3'-非翻訳領域(UTR)の関与

近藤誠二, 久保田聡, 椋代義樹, 森谷徳文, 西田崇, 菅原利夫, 滝川正春

日本骨代謝学会学術集会プログラム抄録集 23回 159 - 159 2005.6

結合組織成長因子CCN2/CTGF/Hcs24はヒト骨髄由来間質細胞の細胞接着を促進させる

大野充昭, 園山亘, 藤澤拓生, 秋山謙太郎, 前川賢治, 完山学, 西田崇, 久保田聡, 滝川正春, 窪木拓男

日本骨代謝学会学術集会プログラム抄録集 23回 225 - 225 2005.6

軟骨由来多機能成長因子CCN2/CTGF/Hcs24は耳介軟骨細胞の形質発現を増強する

藤澤拓生, 中尾匡志, 服部高子, 久保田聡, 窪木拓男, 滝川正春

日本骨代謝学会学術集会プログラム抄録集 23回 262 - 262 2005.6

軟骨細胞における低密度リポタンパク受容体関連タンパク1(LRP1)の遺伝子発現とタンパク質局在

河田かずみ, 江口傑徳, 久保田聡, 川木晴美, 岡森彦, 皆木省吾, 滝川正春

日本骨代謝学会学術集会プログラム抄録集 23回 260 - 260 2005.6

各種軟骨細胞におけるM-CSFの産生とその生理的役割

中尾匡志, 久保田聡, 藤澤拓生, 岡森彦, 江口傑徳, 滝川正春

日本骨代謝学会学術集会プログラム抄録集 23回 177 - 177 2005.6

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Papers - TAKIGAWA Masaharu